Lymphatic Vessel Density at the Site of Deepest Penetration as a Predictor of Lymph Node Metastasis in Submucosal Colorectal Cancer

Purpose Lymph node metastasis is an important factor that influences curability after endoscopic treatment of submucosal colorectal cancer. This study was designed to determine the usefulness of identification of lymphatic vessels by immunohistochemistry in predicting lymph node metastasis of submucosal colorectal cancer. Methods Lymphatic involvement was assessed by hematoxylin and eosin staining and podoplanin immunostaining on samples resected from 268 patients with submucosal colorectal cancer. Lymphatic vessel density was estimated by two investigators by average count of three fields (×200) in the area of greatest number of podoplanin-positive capillaries at the site of deepest submucosal penetration. Relations with other clinicopathologic parameters also were investigated. Results Lesions with high lymphatic vessel density (≥9 vessels per field) showed a significantly greater incidence of lymph node metastasis than did those with low lymphatic vessel density (<9 vessels per field; 23.3 vs. 8.4 percent). By multivariate analysis, lymphatic vessel density was determined to be an independent risk factor for lymph node metastasis of submucosal colorectal cancer (P = 0.0044). Lymphatic vessel density also correlated with tumor budding and the degree of inflammation at the invasive front. Conclusions Identification of lymphatic vessels by podoplanin immunostaining provides objective and accurate evaluation of lymphatic involvement. Lymphatic vessel density at the site of deepest penetration is a useful predictor of lymph node metastasis of submucosal colorectal cancer. Supported by a grant from the Japanese Society of Gastroenterological Endoscopy, Chugoku Branch. Presented at the meeting of The Japanese Society of Gastroenterology, Kokura, Fukuoka, Japan, April 20 to 22, 2006. Reprints are not available.     

Lymphatic Microvessel Density is an Independent Prognostic Factor in Colorectal Cancer

Purpose Although lymph node metastasis via lymphatic vessels often is related with an adverse outcome, it is not well known whether lymphatic spread to lymph node needs the development of the new lymphatic formation. In addition, the correlation between lymphangiogenesis and prognosis has not been well documented. This study was designed to assess the prognostic value of lymphangiogenesis and lymphatic vessel invasion in colorectal cancer. Methods We examined 106 colorectal cancer specimens by immunostaining for podoplanin, lymphatic endothelial specific marker. We evaluated lymphangiogenesis, as measured by lymphatic microvessel density, and lymphatic vessel invasion. We next investigated the association of these two parameters with the clinicopathologic findings and prognosis. Results A significant correlation was observed between high lymphatic microvessel density and positive lymphatic vessel invasion (P = 0.0003). Positive lymphatic vessel invasion was significantly associated with the presence of lymph node metastasis (P = 0.0071). The survival curves demonstrated that both high lymphatic microvessel density and positive lymphatic vessel invasion were correlated with an adverse outcome (P = 0.0004 and P = 0.009, respectively). In a univariate analysis, high lymphatic microvessel density and positive lymphatic vessel invasion were negatively associated with the overall survival (P = 0.0011 and P = 0.0118, respectively). Furthermore, high lymphatic microvessel density, but not lymphatic vessel invasion, correlated with a poor outcome in a multivariate analysis (P = 0.0114). Conclusions Our data suggested that lymphatic vessel invasion was related with lymph node metastasis and that both lymphatic microvessel density and lymphatic vessel invasion were related with an adverse outcome in colorectal cancer. Furthermore, lymphatic microvessel density may be a useful prognostic factor in colorectal cancer. *Deceased. The Poster presentation at the meeting of the Japanese Society of Gastroenterology, Sapporo, Japan, October 11 to 14, 2006. Reprints are not available.     

Vascular endothelial growth factor-C (VEGF-C) is a more specific risk factor for lymph node metastasis than VEGF-D in submucosal colorectal cancer

BACKGROUND/AIMS: It is useful to decide whether lymphatic involvement or lymph node metastasis exists before polypectomy or operation in submucosal colorectal cancer. Whether vascular endothelial growth factor-C (VEGF-C) or VEGF-D could predict lymph node metastasis and lymphatic involvement is uncertain. METHODOLOGY: Expression of the VEGF-C and VEGF-D in human submucosal colorectal cancers was investigated in paraffin-embedded stepwise sections by means of immunohistochemistry, and the correlation between immunohistochemical expression pattern and clinicopathological features was also evaluated. RESULTS: The results showed that VEGF-C overexpression correlated with lymphatic involvement (P = 0.01) and lymph node metastasis (P = 0.02), but VEGF-D overexpression did not correlate significantly. In multivariate analysis lymphatic invasion was the predictive factor (P = 0.0129), but VEGF-C positivity was not predictive (P = 0.3437). CONCLUSIONS: These results may suggest that VEGF-C is a more specific risk factor for lymph node metastasis than VEGF-D in submucosal colorectal cancer.     

Angiogenesis at the site of deepest penetration predicts lymph node metastasis of submucosal colorectal cancer

PURPOSE: Intratumor microvessel count has been reported as a useful prognostic factor in patients with cancer of various organs. This study was undertaken to clarify the relation between microvessel count and lymph node metastasis in submucosal colorectal cancer. METHODS: Microvessel count was estimated in 254 invasive tumors that had been resected from patients with submucosal colorectal cancer. Immunohistochemistry with antibodies against CD34 was performed on archival specimens, and microvessel counts were estimated based on the average count of three fields (original magnification, x400) in the most vascular area at the site of deepest submucosal penetration. RESULTS: Microvessel count ranged from 10 to 98, with a median of 40. Lesions with high microvessel counts (> or =40) had a significantly higher incidence of lymph node metastasis than those with low microvessel counts (<40; 21.8 percent vs. 6.2 percent). None of the 79 lesions with low microvessel counts and submucosal invasion up to a depth of 1,500 microm had metastasized to the lymph nodes. In multivariate analysis, microvessel count was an independent risk factor for lymph node metastasis in submucosal colorectal cancer (P = 0.0026). CONCLUSION: Microvessel count at the site of deepest submucosal penetration can be one of the most useful predictors for lymph node metastasis. Analysis that combines microvessel count and depth of submucosal invasion may predict the occurrence of lesions without lymph node metastasis.     

Management of T1 colorectal carcinoma with special reference to criteria for curative endoscopic resection

Background and Aim: In guidelines 2010 for the treatment of colorectal cancer from the Japanese Society for Cancer of the Colon and Rectum (JSCCR), the criteria for identifying curable T1 colorectal carcinoma after endoscopic resection were well/moderately differentiated or papillary histologic grade, no vascular invasion, submucosal invasion depth less than 1000 µm and budding grade 1 (low grade). We aimed to expand these criteria. Methods: A total of 499 T1 colorectal carcinomas, resected endoscopically or surgically, were analyzed. Relationships between clinicopathologic findings and lymph node metastasis were evaluated. Results: Lymph node metastasis was found in 41 (8.22%) of the 499 cases. The incidence of lymph node metastasis was significantly higher in lesions featuring poorly differentiated/mucinous adenocarcinoma, submucosal invasion ≥ 1800 µm, vascular invasion, and high‐grade tumor budding than in other lesions. Multivariate logistic regression analysis showed all of these variables to be independent risk factors for lymph node metastasis. When cases that met three of the JSCCR 2010 criteria (i.e. all but invasion < 1000 µm) were considered together, the incidence of lymph node metastasis was only 1.2% (3/249, 95% confidence interval: 0.25–3.48%), and there were no cases of lymph node metastasis without submucosal invasion to a depth of ≥ 1800 µm. Conclusions: Even in cases of colorectal carcinoma with deep submucosal invasion, the risk of lymph node metastasis is minimal under certain conditions. Thus, even for such cases, endoscopic incisional biopsy can be suitable if complete en bloc resection is achieved.     

Predictive factors for lymph node metastasis in t1 stage colorectal Carcinomas

Purpose Selective endoscopie resection may cure early colorectal cancer (Tl), but the management is controversial. There is concern about the small risk of lymph node metastasis, which will not be treated by endoscopie resection alone. The authors sought predictive markers of lymph node metastasis to assist patient management. METHODS: The authors retrospectively analyzed consecutive cases of Tl stage colorectal cancer resected using endoscopie resection or bowel surgery over the period 1979 to 2000. The risk of lymph node metastasis was analyzed using logistic regression model for the markers selected by univariate analysis: the type of initial treatment, depth of submucosal invasion, lymphatic channel invasion, differentiation of histology, and invasive front histology. RESULTS: Two hundred seventy-eight patients were available for study. Twenty-one had lymph node metastasis. Depth of submucosal invasion (2 2,000 yum) and lymphatic channel invasion significantly predicted risk of lymph node metastasis in multivariate analysis. When these two factors were adopted for the prediction of lymph node metastasis, sensitivity, specificity, positive predictive value, and negative predictive value were 100, 55.6, 15.6, and 100 percent, respectively. CONCLUSIONS: Depth of submucosal invasion and lymphatic channel invasion were accurate predictive factors for lymph node metastasis. These two factors could be used in selecting appropriate cases for surgery after endoscopie resection. Poster presentation at meeting of the American Society of Colon and Rectal Surgeons, San Diego, California, June 2 to 7, 2001.     

The expression of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and angiogenesis in relation to the depth of tumor invasion and lymph node metastasis in submucosally invasive colorectal carcinoma]

BACKGROUND/AIMS: Lymph node (LN) metastasis occurs in approximately 10% of patients with submucosally invasive colorectal carcinoma. This study was performed to determine the role of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) production and microvessel formation on the LN metastasis in submucosally invasive colorectal carcinoma. METHODS: A total of forty-one subjects with surgically resected submucosally invasive colorectal carcinoma were included in this study. Immunohistochemical staining of MMP-2, MMP-9, TIMP-1, TIMP-2, and urokinase-type plasminogen activator were performed. Angiogenesis was evaluated by counting the number of microvessels in each pathologic specimen as identified by CD34 immunohistochemical staining. RESULTS: The depth of submucosal invasion was not significantly correlated with the expression of MMP-2, MMP-9, TIMP-1, TIMP-2, or urokinase-type plasminogen activator, but the microvessel count was significantly correlated with the absolute depth of invasion (r=0.312, p<0.05). Upregulation of TIMP-2 was positively correlated with adjacent lymphatic invasion (p<0.05) and increased TIMP-2 expression was correlated with LN metastasis in submucosally invasive colorectal carcinoma (p=0.088). CONCLUSIONS: These results suggest that the expression of TIMP-2 and the microvessel count may be useful parameters for considering additional surgery after endoscopic treatment of submucosally invasive colorectal carcinoma.     

Predictive Histopathologic Factors for Lymph Node Metastasis in Patients With Nonpedunculated Submucosal Invasive Colorectal Carcinoma

PURPOSE Risk factors for lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma remain to be characterized. This study examines the relationship between lymph node metastasis and clinicopathologic factors in nonpedunculated submucosal invasive colorectal carcinoma.METHODS The study cohort comprised 155 patients who had undergone surgical treatment for nonpedunculated submucosal invasive colorectal carcinoma. The clinicopathologic factors investigated included gender, age, tumor location, macroscopic type, tumor size, histologic type and grade, intramucosal growth pattern, lymphatic invasion, venous invasion, degree of focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and the depth and width of submucosal invasion.RESULTS Lymph node metastases were found in 19 patients (12.3 percent). Univariate analysis showed that lymphatic invasion, focal dedifferentiation at the submucosal invasive front, status of the remaining muscularis mucosa, and depth of submucosal invasion all had a significant influence on lymph node metastasis. Multivariate analysis showed lymphatic invasion (P = 0.014) and high-grade focal dedifferentiation at the submucosal invasive front (P = 0.049) to be independent factors predicting lymph node metastasis. No lymph node metastasis was found in tumors with a depth of submucosal invasion of <1.3 mm.CONCLUSIONS Lymphatic invasion and high-grade focal dedifferentiation at the submucosal invasive front are important predictors of lymph node metastasis in patients with nonpedunculated submucosal invasive colorectal carcinoma. Depth of submucosal invasion can be used as an identifying marker for patients who do not require subsequent surgery after endoscopic resection.Supported in part by a grant-in-aid for cancer research from the Ministry of Health and Welfare of Japan.     

Risk Factors for Occult Lymph Node Metastasis of Colorectal Cancer Invading the Submucosa and Indications for Endoscopic Mucosal Resection

Purpose Although risk factors for histologically overt lymph node metastasis in patients with early-stage colorectal cancer have been clarified, the risk factors for occult lymph node metastasis are not clear. This study was designed to clarify risk factors for lymph node metastasis, including occult metastasis, in patients with colorectal cancer invading the submucosa and to determine the criteria for endoscopic resection of early colorectal cancer. Methods The risk factors for lymph node metastasis, including occult metastasis, were analyzed in 86 cases of surgically resected colorectal cancer invading the submucosa. The lymph nodes were assessed by immunohistochemistry with cytokeratin antibody CAM5.2. Results The frequencies of overt and occult metastasis to the lymph nodes were 13 percent (11/86) and 13 percent (10/75), respectively. Multivariate analysis showed vascular invasion (P = 0.001) and tumor budding (P = 0.003) to be independent risk factors for lymph node metastasis, including occult metastasis. For tumors with submucosal invasion ≤1,000 μm, no lymph node metastasis was found. The frequencies of lymph node metastasis for tumors with submucosal invasion of 1,000 to 2,000 μm and >2,000 μm were 21 and 37 percent, respectively. In considering combinations of risk factors, there was no lymph node metastasis in tumors having neither vascular invasion nor tumor budding and submucosal invasion of ≤3,000 μm. Conclusions Vascular invasion, tumor budding, and the degree of submucosal invasion were significant risk factors for lymph node metastasis, including occult metastasis. These three factors can be used in combination to identify patients requiring additional surgery after endoscopic resection. Supported in part by a Grant-in-Aid for Scientific Research (no. 15390401) from the Japanese Ministry of Education, Science, and Culture. Presented at the Congress of Japan Surgery Society, Tokyo, Japan, March 29 to 31, 2006. Reprints are not available.     

Predictive value of histology at the invasive margin in the prognosis of early invasive colorectal carcinoma

To accurately select patients with malignant colorectal polyps who are at high risk of adverse outcome, we examined the predictive value of clinicopathological factors, with special attention paid to the histology at the invasive margin. We examined 75 submucosal carcinomas from 75 patients, initially resected by polypectomy, including endoscopic, trans-anal, trans-sacral, and trans-sphincteric local excision. The associations between clinicopathological features such as sex and age; tumor size, location, shape, depth of submucosal invasion, vascular invasion, histology at the central part, and histology at the invasive margin; and the presence or absence of a residual adenomatous component and adverse outcome were examined by univariate and multivariate logistic regression analyses. Lymph node metastases were found in 2 patients, local recurrence in 4, and distant metastases in 2. Univariate logistic regression analysis showed that unfavorable histology at the invasive margin was significantly associated with lymph node metastasis or local recurrence (P = 0.0373), whereas the association of lymphatic invasion and vascular (lymphatic or venous) invasion with lymph node metastasis or local recurrence had marginal significance (P = 0.0785; P = 0.0990). Multivariate logistic regression analysis, with unfavorable histology at the invasive margin and lymphatic invasion as independent variables, showed that unfavorable histology alone had significance (P = 0.0373) in predicting adverse outcome. Widely accepted criteria such as massive submucosal invasion, positive vascular invasion, and poorly differentiated histology, were less useful in predicting adverse outcome. These results suggest that unfavorable histology at the invasive margin is a useful risk factor for predicting lymph node metastasis or local recurrence in patients with malignant colorectal polyps. Received: March 23, 1999 / Accepted: August 27, 1999     

Lymphangiogenic and angiogenic microvessel density in human primary sporadic colorectal carcinoma

AIM： To investigate the distribution pattern of lymphatic vessels and microvessels in sporadic colorectal carcinoma （SCRC） and their relationship to metastasis and prognosis. METHODS： The lymphatic vessel density （LVD） and microvessel density （MVD） in tumor tissue obtained from 132 patients with primary SCRC, including 74 with metastases and 58 without metastases, were evaluated by immunohistochemistry using antibodies directed against D2-40 and yon Willebrand factor （vWF）. RESULTS： （1） The lymphatic vessels and microvessels at central portions of SCRC often had a reticular architecture with numerous tiny and ill-defined lumina, while those at tumor borders had large and open lumina. The LVD and MVD were both obviously higher in colorectal cancer patients with metastases than in those without （P 〈 0.001）. （2） For each one lymphatic vessel increased, there was a 1.45-fold increase in the risk of metastasis in SCRC. The specificity and sensitivity of LVD in predicting metastasis or non-metastasis in SCRC were 71.62% and 56.90%, respectively, and the corresponding LVD was 5. For each one microvessel increased, there was a 1.11-fold increase in the risk of metastasis in SCRC. The specificity and sensitivity of MVD were 66.22% and 51.72%, respectively. （3） Double labeling immunohistochemistry showed D2-40 immunoreactivity to be specific for lymphatic vessels. （4） Univariate analysis indicated that high LVD, high MVD, as well as co-accounting of high LVD and high MVD were associated with patient＇s poor disease-free survival （Puni 〈 0.05）; multivariate analysis indicated that co-accounting of LVD and MVD was an independent prognostic factor of colorectal cancer, CONCLUSION： D2-40 is a new specific antibody for lymphatic endothelial cells. Lymphogenesis and angiogenesis are commonly seen in SCRC, especially at tumor borders. The detection of LVD and MVD at tumor borders may be useful in predicting metastasis and prognosis in patients with SCRC, and, in particular, coa     

大肠癌粘膜下浸润类型与癌转移及凝集素受体表达关系的研究

本文观察了76例大肠癌粘膜下浸润方式，表明间隙浸润型和淋巴小结浸润型者分别占42．1％和11．8％，血管浸润或淋巴管润型分别占21．1％和25．8％。组织病理学分析表明，大肠癌的分布部位和分化程度与粘膜下浸润类型无关，但血管或淋巴管浸润者，其癌细胞浸润深度和转移癌的发生明显比间隙或淋巴小结浸润型为高。应用荆豆凝集素（UEA－Ⅰ）免疫组化技术要使血管内皮层着染，因而可容易辨认血管浸润的癌细胞团。对癌细胞UEA－Ⅰ和PNA受体表达的分析表明，粘膜下各浸润型大肠癌，其凝集素受体表达阳性率及PNA阳性细胞量和染色强度，类型，无明显差别，但UEA－Ⅰ的表达在血管或淋巴浸润型者呈减少趋势，提示用内镜活检粘膜标本综合评价肿瘤病变预估病变进展有参考意义。     

Curative Resection of T1 Colorectal Carcinoma: Risk of Lymph Node Metastasis and Long-Term Prognosis

PURPOSE The features of T1 colorectal adenocarcinoma and the risk determination of lymph node metastasis were reviewed. Prognostic factors were assessed to verify whether the risk of lymph node metastasis would influence the long-term prognosis.METHODS Patients undergoing curative resection of T1 colorectal adenocarcinoma at the Taipei Veterans General Hospital from December 1969 to August 2002 were retrospectively studied. Patients with synchronous colorectal cancer, distant metastasis, familiar adenomatous polyposis, or inflammatory bowel disease were excluded. The associations between lymph node metastasis and clinicopathologic variables were evaluated univariately using chi-squared test, Fisher’s exact test, or Student’s t -test, and multivariately using logistic regression. Univariate analysis by the log-rank test and multivariate analysis by Cox regression hazards model determined the factors influencing the overall survival.RESULTS A total of 159 patients were included. Sixteen patients (10.1 percent) had lymph node metastasis. The risk of lymph node metastasis included histologic grade (P = 0.005), lymphatic vessel invasion (P = 0.023), inflammation around cancer (P = 0.049), and budding at the invasive front of tumor (P = 0.022). Age (P = 0.001) and number of total sampling lymph nodes (P < 0.0001) were found to be the factors influencing the overall survival.CONCLUSIONS Variables that predict lymph node metastasis in surgically resected T1 colorectal carcinoma may not impact the long-term prognosis.Supported by a grant from the Research Foundation of Taipei Veterans General Hospital.     

Clinical Usefulness of D2-40 in Non-Small Cell Lung Cancer

D2-40 is a recently developed monoclonal antibody that reacts with a 40 kDa O-linked sialoglycoprotein and has been used for the assessment of lymphatic invasion in tumor specimens. We have evaluated the diagnostic usefulness of D2-40 and association of its immunopositivity with clinicopathological parameters in adenocarcinoma and squamous cell carcinoma of the lung. We investigated 97 cases of surgically resected adenocarcinoma or squamous cell carcinoma of the lung for the determination of D2-40 positivity in tumor cells and peritumoral lymphatic vessel density (LVD) using an immunostaining method. D2-40 immunoreactivity in tumor cells was invariably negative in adenocarcinoma but 47% of squamous cell carcinomas were positive. D2-40 positivity in the tumor was significantly associated with high LVD in squamous cell carcinoma (P < 0.006). There was no significant association between peritumoral LVD and clinicopathologic parameters, including lymphatic vessel invasion, lymph node metastasis, and survival in adenocarcinoma and squamous cell carcinoma. These results suggest that D2-40 immunoreactivity in tumor cells can be used for distinguishing between adenocarcinoma and squamous cell carcinoma and that the reactivity of tumor cells with D2-40 is positively correlated with LVD in squamous cell carcinoma but not with lymph node metastasis in adenocarcinoma and squamous cell carcinoma.     

Clinicopathological study for reevaluation of the depth of submucosal invasion and histological classification of early colorectal cancer]

The following studies were undertaken using specimens of submucosal invasive colorectal cancer surgically or endoscopically resected from 104 patients: 1) measurement of the depth of submucosal invasion; 2-a) histological reevaluation of colon sm cancer by scoring of the degree of histological differentiation using a modified Gleason's grading system proposed for prostatic cancer; and 2-b) immunohistological evaluation of E-cadherin, a cell adhesion factor. Lymphatic node metastasis occurred in no case with the depth of submucosal invasion of less than 1,000 microns. In the histological reevaluation, high incidence of lymphatic metastasis was noted in the high-score group, while lymphatic node metastasis was not seen in any patients in the low-score group. Immunohistological evaluation of E-cadherin showed that the destructive pattern is correlated with lymphatic metastasis, suggesting that weakening of the cell adhesive factor was related to a decline in the degree of differentiation of the tumor. Findings obtained in the present study suggest that endoscopic therapy is indicated for colon cancer measuring less than 1,000 microns and that its indication can be expanded to colorectal cancer with the depth of submucosal invasion of more than 1,000 microns by adding histological reevaluation.     

Evaluation of Tumor Cell Dissociation as a Predictive Marker of Lymph Node Metastasis in Submucosal Invasive Colorectal Carcinoma

PURPOSE Tumor cell dissociation—the histologic finding of small solid carcinoma cell clusters and groups of dissociated dedifferentiated carcinoma cells at the invasive front–is related to tumor metastasis and patient prognosis. However, few previous reports have examined tumor cell dissociation in submucosal invasive colorectal carcinoma. We investigated the relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. We also examined immunohistochemical expression of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma.METHODS Submucosal invasive colorectal carcinoma tissue samples from 20 patients with lymph node metastasis and 100 patients without lymph node metastasis were evaluated. Sections stained with hematoxylin and eosin were evaluated for tumor cell dissociation. Immunohistochemistry was used to determine the expression and cellular distribution of E-cadherin and beta-catenin.RESULTS Tumor cell dissociation was more frequently identified in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.0001). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.025). Nuclear expression of beta-catenin tended to be present in submucosal invasive colorectal carcinoma cases with lymph node metastasis (P = 0.063). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with tumor cell dissociation than in those without tumor cell dissociation (P = 0.0023).CONCLUSIONS Our results suggest that there is a relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. Tumor cell dissociation formation might be related to abnormal expression patterns of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma. Tumor cell dissociation and decreased membranous expression of E-cadherin would be important predictive markers for lymph node metastasis in submucosal invasive colorectal carcinoma.Presented at the 93rd Japanese Society of Pathology, Sapporo, Japan, June 9 to 11, 2004.     

Immunohistochemical localization of carcinoembryonic antigen as a predictor of lymph node status in submucosa-invasive colorectal carcinoma

PURPOSE: Submucosa-invasive colorectal carcinoma is a colorectal carcinoma extending only into the submucosal layer. To clarify the metastatic potential of submucosa-invasive colorectal carcinoma, we studied the relationship between the immunohistochemical staining pattern of carcinoembryonic antigen (CEA) and that of lymphatic invasion/ lymph node metastasis. METHODS: We investigated 49 submucosa-invasive colorectal carcinomas resected surgically or endoscopically. CEA distribution patterns of the neoplastic tissues were divided into three patterns: Pattern 1 = luminal type; Pattern 2 = apical cytoplasmic type; and Pattern 3 = diffuse cytoplasmic type. We also observed the submucosal stromal staining of CEA. RESULTS: Lymphatic invasion and lymph node metastasis were found in 48.8 percent (21/43) and 11.6 percent (5/43) of the Pattern 2/Pattern 3 cases, whereas these were seen in none (0/6) of Pattern 1 cases. Lymphatic invasion and lymph node metastasis were found in 63.3 percent (19/30) (chi-squared =21.94;P <0.001) and 16.7 percent (5/30) of the positive stromal CEA cases, whereas these were seen in 10.5 percent (2/19) and none (0/14) of the negative stromal CEA cases, respectively. CONCLUSION: Pattern 2/Pattern 3 and stromal CEA can be predictors of the lymph node metastasis with 11.6 percent and 16.7 percent risks.Read at the meeting of the Japanese Society of Gastroenterological Surgery, Tokyo, Japan, February 24 to 25, 1994.     

Clinical significance of lymph vessel density in T3 colorectal carcinoma

Purpose

The purpose of the present study is to characterise the lymphatic vessel density (LVD) in the T3 colorectal carcinoma and to correlate it with N status, grading and presence of tumour budding.

Methods

A total of 56 cases of T3 colorectal carcinoma were retrieved from the pathology’s archive of Klinikum Augsburg. All slides were stained immunohistochemically with D2-40 (lymphatic endothelium) and with pancytokeratin to assess the tumour budding. Tumour budding and lymph vessel density were investigated independently by BM and CC. The highest density of lymphatic vessels was counted both in tumour centre (ILVD) and at the periphery of the tumour (PLVD) within an area of 0.24?mm².

Results

Due to the strong intra-observer (BM and CC) difference in ILVD and PLVD, all cases were re-evaluated establishing a consensus that has been used for the further analyses. There was a significant difference between PLVD and ILVD (12?±?4 versus 6?±?3; P?P?=?0.072). There was no association between tumour budding and ILVD and PLVD (P?=?0.249 and 0.38).

Conclusion

Colorectal carcinoma induces lymphangiogenesis. A higher PLVD could increase the capability of cancer cell to invade the lymphatic system. However, the obvious difficulties in immunohistochemical evaluation and the rather small differences between nodal positive and negative cases in T3 colorectal cancer seem to limit the clinical value of LVD evaluation.     

Lymphatic vessel invasion detected by monoclonal antibody D2-40 as a predictor of lymph node metastasis in T1 colorectal cancer

Objective  When selecting patients who are at high risk for lymph node metastasis, the detection of lymphatic vessel invasion (LVI) is important. We investigated LVI detected by D2-40 staining as a predictor of lymph node metastasis in T1 colorectal cancer. Materials and methods  Clinicopathological factors including LVI were investigated in 136 patients who underwent colectomy with lymph node dissection for T1 colorectal cancer. We used immunostaining with monoclonal antibody D2-40 to detect LVI. Results  Lymph node metastases were found in 18 patients (13.2%), and LVI were detected in 45 (33%); lymph node metastasis was more frequently observed in LVI-positive groups (13/45 vs 5/91, p < 0.001). Both univariate and multivariate analyses revealed that LVI detected by D2-40 and a poorly differentiated histology at the invasion front were independent risk factors of lymph node metastasis. Conclusion  LVI detected by D2-40 is important for the prediction of lymph node metastasis.     

Involvement of cyclooxygenase-2 and vascular endothelial growth factor in vascularization and lymph node metastasis of colorectal cancers with submucosal invasion

BACKGROUND AND AIMS: Although patients with early colorectal cancer invading the submucosa (CRC-sm) may be treated with endoscopic mucosal resection alone, they generally undergo additional surgery because of the risk of lymph node metastasis. The aims of the present study were to examine the roles of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in tumor vascularization and to investigate whether COX-2 and VEGF expression and tumor vascularity are useful markers for predicting lymph node metastasis in CRC-sm. METHODS: Twenty-seven resected specimens of CRC-sm with lymph node dissection were examined, and expression of COX-2 and VEGF was evaluated immunohistochemically and scored. Microvessel density (MVD) in CRC-sm tissues was estimated using a Macscope system after CD34 immunostaining. The relationships among clinicopathological parameters, COX-2 and VEGF expression, and MVD in CRC-sm tissues were then analyzed. RESULTS: Scores for COX-2, VEGF and MVD were all significantly higher in patients with CRC-sm with lymphatic invasion or lymph node metastasis. COX-2 score (P < 0.0001) and VEGF score (P = 0.035) were significantly correlated with MVD in CRC-sm tissues. In addition, COX-2 score was significantly correlated with VEGF score in the CRC-sm specimens examined. CONCLUSIONS: Both COX-2 and VEGF are involved in tumor vascularization in CRC-sm. COX-2 expression, VEGF expression, and MVD are possible markers for predicting lymph node metastasis in patients with CRC-sm, and use of COX-2 expression may be clinically practical.